The pathophysiologic model for heart failure (HF) has advanced from a simple hemodynamic model to a more complicated model that includes neurohormonal and cytokine components. Proinflammatory cytokines, which are expressed earlier than neurohormones, play a critical role in extracellular matrix turnover, including the regulation of matrix metalloproteinases (MMPs). Currently, there are no approved medications that directly target tumor necrosis factor (TNF) -a or MMPs. Increased expression of TNF-a and MMP is associated with maladaptive cardiac remodeling and has been identified as an independent predictor of survival in HF patients. Sub-antimicrobial doxycycline (SDD) has been shown to reduce TNF-a and MMPs in other chronic diseases but has not been evaluated in HF patients due in part to it no longer having patent protection and being sold as a generic drug. The Sub-antimicrobial Doxycycline Therapy on Outcomes of Physical Function and Patterns of End-Diastolic Volume in Heart Failure Patients (STOPPED-HF) Study is a double blinded randomized prospective phase 2 clinical trial of the effects of SDD in a cohort of 200 HF subjects with reduced left ventricular function. The primary hypothesis is that SDD will significantly reduce left ventricular end diastolic volume index changes in HF patients over 12 months of treatment. In addition, SDD will improve physical function and quality of life; and reduce MMP and tumor necrosis factor alpha. Adverse drug reactions will also be followed as part of the study. The STOPPED-HF study is the scientific protocol proposed by the Jefferson Regional Clinical Center (RCC) for its application to participate in the NHLBI's Heart Failure Clinical Research Network. The Jefferson RCC brings together 3 of the largest healthcare systems in the Delaware Valley: Thomas Jefferson University (Pl: Dr. David Whellan; co investigator Dr. Raphael Bonita), Temple University (co-investigator: Dr. Alfred Bove) and Christiana Care (co-investigator: Dr. Mitchell Saltzberg). These centers will offer participation i HF Network protocols to a large HF patient population, including a significant minority and female population. Recognizing the goal of including HF patients with preserved LV function, the application includes participation of the Department of Family Medicine (co-investigator; Dr. Geoffrey Mills). The Jefferson RCC will leverage its participation in the HF Network, the established K30 program and world-renowned HF researchers to establish the Jefferson Clinical Research Skills Development Core (Core Leader: Dr. Walter Kraft; mentors: Drs. Arthur Feldman, Thomas Force, Paul Mather and David Whellan). RELEVANCE (See instructions): Enhancing the pipeline of new therapies for heart failure patients is critical to reducing the high morbidity and mortality that this patient population continues to suffer. Evaluating low-cost treatments, such as the generically available sub-antimicrobial dosing of doxycycline, in smaller phase 2 clinical trials provides the necessary data to inform researchers and funding agencies prior to organizing larger clinical trials.